This paper critically reviews the evaluative literature on programs and other interventions designed to prevent substance-use problems among youth. We start from a description and discussion of patterns and trends in youthful drug use, and evidence on types of harm. We then describe and assess the literature evaluating programs and initiatives to prevent youthful drug problems. The following headings were used: Education & Persuasion, Community-Based, Legal and Regulatory Policies, and Harm Reduction. Lastly, in the light of this review, we offer some commentary and analysis concerning the reality of program goals, theoretical underpinnings, and cost-effectiveness. We conclude with recommendations for future prevention strategies.